Ultraviolet (UV) radiation represents a definitive risk factor for skin cancer, particularly in combination with certain underlying genetic traits, such as red hair and fair skin. Skin pigmentation results from the synthesis of melanin in pigment-producing cells, the melanocytes, followed by distribution and transport of the pigment granules to neighboring keratinocytes. Epidemiological studies have found less skin cancer in people who have high levels of constitutive pigment and/or tan well. However, we have incomplete understanding of other factors involved in the development of skin cancer, such as capacity to repair photo- damage in people of different skin colors. The finding that albinos have a lower incidence of melanoma than people with fair skin makes this question more complex. Recent findings including our own have led to a realization that melanin, especially pheomelanin (a yellow/red form of melanin), acts as a potent UVB photosensitizer to induce DNA damage and cause apoptosis in mouse skin. The proposed research will focus on the role of pheomelanin in DNA damage, at both genomic and individual nucleotide levels, and on the subsequent activation of DNA repair, alteration in chromatin structure, and ultimately melanoma formation. We hypothesize that pheomelanin contributes to UV-induced DNA damage that is incompletely repaired. Although DNA repair may be activated to a larger extent in response to the greater DNA damage in pheomelanin-containing skin, the repair will be insufficient to eliminate all mutagenic adducts. We will first identify the role of pheomelanin in melanoma formation by melanoma mouse models. Second, we will define the photoproducts and oxidative stress to DNA in mice with different type of epidermal pigmentation at different times after UVB irradiation by quantitative methods. Third, we will map DNA damage in specific sequences of BRAF and N-RAS genes, both of which are frequently mutated in human melanoma. Finally, we will detect the expression of genes in DNA repair pathways at different times after UVB irradiation. Given the vital role that pheomelanin plays in normal phototoxicity and disease, these studies will provide important insights into the homeostasis of tanning and the pathogenesis of disorders like melanoma. Expanding our knowledge of DNA repair in different skin types provides a rich ground for melanoma prevention and for the development of targeted small-molecule therapeutics. PUBLIC HEALTH RELEVANCE: Melanoma prevention is defined as the reduction of melanoma mortality via reduction in the incidence of melanoma. Our results may provide a rich framework for melanoma prevention;and development of targeted small-molecules to induce eumelanin (black/brown), and hence an eventual reduction in incidence of this widely lethal malignancy.